Use of ZT-1A and analogs thereof to prevent and/or treat neurodegenerative and neurocognitive disorders
Inventors
SUN, Dandan • Bhuiyan, Mohammad Iqbal Hossain
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11925611-B2
Publication Date
2024-03-12
Expiration Date
2042-03-25
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present disclosure is concerned with substituted N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds, and methods of treating and/or preventing neurodegenerative or neurocognitive disorders including, but not limited to, Alzheimer's disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), Multiple Sclerosis, spinal muscular atrophy, spinal and bulbar muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease, and dementia (e.g., vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, dementia induced by Alzheimer's disease or Parkinson's disease). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to substituted N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds that are useful in treating and preventing neurodegenerative and neurocognitive disorders. These disorders include Alzheimer's disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Multiple Sclerosis, spinal muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, Lewy body disease, and various forms of dementia such as vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, and dementia induced by Alzheimer's or Parkinson's disease.
The problem addressed by the invention is the lack of effective therapies for dementia and other neurocognitive disorders that often result from stroke and other causes of white matter injury. Vascular dementia, primarily characterized by diffuse white matter lesions and axonal damage, has no known treatment, partly due to unknown molecular and cellular mechanisms underlying white matter injury. The invention meets the need for compounds and methods to treat and prevent dementia and neurodegenerative diseases by utilizing compounds that modulate SPAK kinase function, particularly through inhibition.
Claims Coverage
The patent contains two independent claims focused on methods of treating and preventing neurodegenerative and neurocognitive diseases using specific substituted benzamide compounds.
Method for treating and preventing neurodegenerative or neurocognitive diseases
Administering to a subject in need an effective amount of a compound having a specified substituted N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide structure, featuring halogen substitutions at X1 and X2, varied R1 groups selected from —OH, —SH, and —NH2, and independently selected substituents at positions R2a-d and R3a-d with various alkyl, haloalkyl, and other functional groups, excluding certain specified compound structures and their pharmaceutically acceptable salts.
Method of treating and preventing dementia
Administering to a subject in need an effective amount of a compound having a specified substituted benzamide structure characterized by halogen substitutions and defined substituents at R groups, as detailed for the neurodegenerative treatment method, specifically applied to dementia treatment and prevention, with exclusion of certain compounds and their pharmaceutically acceptable salts.
The claims protect methods of preventing and treating a wide range of neurodegenerative and neurocognitive diseases, particularly using specifically substituted benzamide compounds that inhibit or modulate SPAK kinase function, with detailed structural definitions and exclusions to define the inventive scope.
Stated Advantages
The compounds reduce white matter demyelination and loss of oligodendrocytes and precursor cells, thus preserving white matter integrity.
Administration of the SPAK inhibitor ZT-1a improves cognitive functions, such as memory and learning, in animal models of cerebral hypoperfusion.
Delayed administration of the inhibitor remains effective in improving memory deficits, myelination, and cerebral blood flow, suggesting therapeutic potential even after the onset of injury.
Documented Applications
Treatment and prevention of neurodegenerative diseases including Alzheimer's disease, CADASIL, Parkinson's disease, Huntington's disease, ALS, Multiple Sclerosis, spinal muscular atrophy, familial spastic paraparesis, Machado Joseph disease, Friedreich's ataxia, and Lewy body disease.
Treatment and prevention of neurocognitive diseases such as various types of dementia, including vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, and dementia induced by Alzheimer's disease or Parkinson's disease.
Interested in licensing this patent?